Abstract Several protective mechanisms have evolved to ensure survival of cells under adverse condition. `Heat Shock Response' is one such survival mechanism. We have previously shown that heat shock protein-70, a multi-faceted chaperone protein protects pancreatic acinar cells from damage during acute pancreatitis. We have extended these observations to pancreatic cancer and have demonstrated that (HSP70) is overexpressed in pancreatic cancer cells and plays a very prominent role in protecting cancer cells from cell death. While previous research focused primarily on the properties of the cancer cell, there has recently been increased understanding of the role of the tumor microenvironment (TME) in supporting cancer growth. Pancreatic cancer has an intricate TME, which is believed to contribute to its aggressive behavior. While studies in non-pancreatic tumors suggest that lack of Heat Shock Factor-1 (HSF1) in stroma decreases the growth of, the role of heat shock response pathway in shaping the TME of pancreatic cancer has never been studied. Intriguingly, our data suggest that triptolide, a natural heat shock inhibitor modulates pancreatic cancer TME and depletes stroma. Our preliminary data also suggest that lack of HSP70 in stromal cells is associated with increased cytotoxic T cell infiltration. Furthermore, we have shown that depletion of HSP70 in immune cells, the other important component of TME, decreases growth of tumors and that T cells lacking HSP70 are more effective in killing pancreatic cancer cells in vitro. These data suggest that Heat Shock Response/ HSP70 in various components of TME (immune vs stroma) influence tumor growth and that triptolide could influence TME by modulating heat shock response. The current grant is focused towards understanding the role of Heat shock response in biology of pancreatic cancer. In specific aim 1 we will confirm the role of stromal HSP70 and Heat Shock Response (HSR) in pancreatic cancer growth using a variety of animal models of pancreatic cancer as well as human specimens. In aim 2, we will elucidate the mechanism by which HSP70 and heat shock response in tumor stroma promotes tumor growth. Specifically, we will elucidate if lack of stromal HSR leads to increased efficacy of immune cells against cancer cells. Finally, in aim 3, we will elucidate the mechanism(s) by which HSP70 and HSR in immune cells promote pancreatic cancer growth. Specifically, we will evaluate whether HSP70/HSR in T cells affect T cell activation and T cell mediated killing. We believe that elucidation of the mechanism by which HSP70/HSR in TME modulate pancreatic cancer progression will lead to increased comprehension of the mechanism cancer cell uses to evade cell death.